Germanium-containing compounds are widely used in diverse fields of science and engineering, for example as semiconductors and catalysts for the production of polyesters and polyolefins, in manufacturing optical fibers for telecommunication facilities and lenses and glasses for IR spectroscopy.
Recently germanium compounds have also come into use in medicine due to their pharmacological activities. The biological properties of germanium compounds include the ability to ensure oxygen transport in tissues of the body and to enhance the immune status of the body, and anti-tumor activities.
Germanium compounds are used in two main forms, namely in an organic form (containing Ge—C bonds) or in an inorganic form (as salts, germanium oxides, and complex compounds thereof). For example, U.S. Pat. No. 4,271,084 (1981, IPC: C 07F 7/30) protects germanium-containing organic polymers, namely carboxyethyl germanium sesquioxides, which are produced by the polymerization of 3-trichlorogermylpropionic acid. The feedstock is germanium dioxide, which is reduced with hypophosphorous acid (H3PO2) in the presence of hydrochloric acid, whereby producing a germanium chloride-phosphoric acid complex. The thus-produced complex compound is converted to 3-trichlorogermylpropionic acid by reaction with acrylic acid (CH2═CHCOOH). The U.S. Pat. No. 5,386,046 (1995, IPC: C07F 7/30) discloses carboxyethyl germanium sesquioxides, which are produced using germanium tetrachloride, tetramethyldisiloxane, and acrylic acid. The prior-art germanium-containing organic polymers are efficient in the treatment of neuropsychiatric disorders (see U.S. Pat. No. 4,281,015, 1981, IPC: A61K 31/28), ophthalmic disorders (see U.S. Pat. No. 4,296,123, 1981, IPC: A61K 31/28), disorders of the liver (see U.S. Pat. No. 4,309,412, 1982, IPC: A61K 31/74), lung fibrosis (see U.S. Pat. No. 4,321,273, 1982, IPC: A61K 31/28), allergic diseases (see U.S. Pat. No. 4,322,402, 1982, IPC: A61K 31/74), and hepatitis (see U.S. Pat. No. 5,340,806, 1994, IPC: A61K 31/79). They also promote the production of interferon in the human body (see U.S. Pat. No. 4,473,581, 1984, IPC: A61K 31/28) and protect it from the cold (see U.S. Pat. No. 4,898,882, 1990, IPC: A61K 31/28).
The U.S. Pat. No. 3,825,546 (1974, IPC: C07D 29/28) describes the preparation of germanium-containing azaspirans (nitrogen-containing heterocyclic compounds), referred to as spirogermaniums. The process of producing spirogermanium is a multi-step synthesis, wherein the initial compound is dialkylgermanium, namely dimethyl- or diethylgermanium (R2GeH2). Dialkylgermanium is transformed into 4,4-dialkyl-4-germa-cyclohexanone in two steps using methyl acrylate, potassium tert-butoxide, and 20% sulfuric acid solution. Following this, spirogermanium is obtained from 4,4-dialkyl-4-germa-cyclohexanone in several steps.
The U.S. Pat. No. 4,468,393 (1984, IPC: A61K 31/555) shows that spirogermanium compounds, especially diethylspirogermanium and salts thereof, are useful for the treatment of arthritis by means of injections or oral administration. Intravenous injection doses of spirogermanium are between 50 and 80 mg/m2 body surface. The therapeutic dose of spirogermanium recommended for treating arthritis with severe rheumatoid symptoms is 1.5 mL aqueous solution (30 mg/mL) intramuscularly. This therapy is to be carried out twice a week during the first six weeks and once a week after remission is achieved. This usually takes a period of three to six months. Oral treatment can be efficient when capsules containing 200 mg spirogermanium are administered twice daily for two weeks and then once daily for six weeks.
The above-described methods for the preparation of germanium-containing organic compounds are multistep and intricate processes. They require that organic solvents be used to isolate and purify target compounds. For example, hydrolysis and condensation of 3-trichlorogermylpropionic acid depend on the process duration and other factors, and this affect the qualities of the final product. The synthesis of spirogermanium comprises five steps, as a result of which the final product yield based on the initial compounds is very low.
Processes are also known for preparing germanium-containing organic compounds that are the products of reacting germanic acid or an alkali-metal salt of metagermanic acid with some amino acids or organic acids. For example, U.S. Pat. No. 3,674,823 (1972, IPC: C07F 7/00) proposes an invention which relates exclusively to a compound of germanic acid and cysteine in the molar ratio 1:1. This compound is active in the treatment of hepatitis, rheumatism, and hydro eczema. The compound is prepared by dissolving a water-soluble form of germanium dioxide in hot water thereby forming germanic acid, then filtering the solution, adjusting pH to 4, and adding cysteine to the aqueous solution of germanic acid. Following this, the solution is heated for 2 hours, then filtered and concentrated by distillation. The product is isolated from the concentrated solution upon cooling. The product can also been isolated by adding ethanol or acetone to the solution. U.S. Pat. No. 3,674,823 does not disclose the feasibility to obtain germanium compounds with other amino acids.
The process for the preparation of germanium compounds that are the product of reacting a potassium or sodium salt of metagermanic acid with some carboxylic acids or amino acids, as disclosed in the patent DE 3212817, 1983, IPC: C07F 7/30, constitutes the most pertinent piece of prior art for our claimed method, and we take it as such. The method for the preparation of germanium compounds as disclosed in the patent DE 3212817 consists in heating germanium oxide with a concentrated aqueous solution of potassium or sodium hydroxide so as to convert the germanium dioxide into a soluble potassium or sodium salt of metagermanic acid; concentrating, cooling, and then suspending the mixture in water under heating with a carboxylic acid, a mixture of carboxylic acids, or an amino acid. The product is obtained in the form of a ready-for-use solution, or is precipitated from the solution by adding an alcohol. Useful amino acids are such as aspartic acid and glutamic acid; useful carboxylic acids include citric acid, isocitric acid, succinic acid, ketoglutaric acid, and fumaric acid; hydroxycarboxylic acids (lactic acid or ascorbic acid) can also be used. The resulting compounds, which are the product of reaction between an alkali-metal salt of metagermanic acid and the aforementioned acids and amino acids, are well soluble in water and have biological and pharmacological properties.
In the patent DE 3212817, the toxicity of germanium compounds with succinic acid and citric acid was studied in mice by the Litchfield and Wilcockson method. For intraperitoneal administration, LD50 was 275 mg/kg and >2 500 mg/kg, respectively. The above-described compounds were subjected to the Allium test. Seeds of onion (Allium cepa) were incubated on Petri dishes. When the roots of germinating onion reached 1 cm length, they were transferred to Petri dishes containing aqueous solutions of the test compounds wherein germanium concentrations were 0.0625%, 0.125%, 0.25%, and 0.5%. The results clearly demonstrated that the germanium compounds have a cytostatic effect, which is associated with a decrease in the mitotic cycle. The germanium compound with aspartic acid was tested in six in-hospital patients who were diagnosed as having oval cancer and malignant tumors of the uterus. The patients received orally 100 mg of the substance in the form of a 10% solution twice daily. The tumors were removed surgically. All patients showed a noticeable improvement in health. In addition, five patients did not show exudate either in the abdominal cavity, or in the internal pelvic cavity. Small exudate was found only in one patient. There were no toxic side effects. None patients showed infiltration in post-operational examination carried out one month later.
The method disclosed in the patent DE 3212817 has the following drawbacks:                Not only does the use of potassium and sodium hydroxides for transferring germanium dioxide into a soluble form through the formation of potassium or sodium salts of metagermanic acid complicate the process, but this is also responsible for the occurrence of alkali-metal cations in the final products, and this can be undesired in the pharmacological use of the resulting compounds;        Germanium complex compounds with acids are frequently stable only in aqueous solution and are destroyed in an attempt at being isolated from water; in the patent DE 3212817, a germanium compound with succinic acid is isolated only in Example 1; the other examples produce solutions of germanium with aspartic and carboxylic acids, and this may serve as evidence of their instability in a solid form and the impossibility of being isolated from aqueous solution;        In view of the fact that the final products obtained in Examples 2 to 4 are solutions, the resulting aqueous solutions containing organogermanium compounds are mixtures comprising potassium or sodium salts of metagermanic acid, carboxylic acids, and germanium compounds with carboxylic acids; medical uses of such an aqueous solution that contains the target product is difficult because of the occurrence therein of the aforementioned contaminants;        The preparation of organogermanium compounds with amino acids is exhausted by the use of aspartic acid (see Example 3)        